CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production

Abstract

Background Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677. Methods The MK2 inhibitor CC-99677 was evaluated for its effect on cytokine expression in vitro in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with a definitive AS diagnosis. A novel in vitro model was developed to compare the potential for tachyphylaxis of CC-99677 and p38 inhibitors in THP-1 cells. The effect of CC-99677 on tristetraprolin (TTP) and cytokine mRNA was assessed in stimulated human monocyte-derived macrophages. In a first-in-human study, thirty-seven healthy volunteers were randomly assigned to daily oral doses of CC-99677 or placebo, and blood was collected at pre-specified time points before and after dosing. CC-99677 concentrations were assessed in the plasma, and CC-99677 binding to MK2 was evaluated in PBMCs. Ex vivo stimulation of the whole blood was conducted from participants in the first-in-human study to assess the pharmacodynamic effects. Results In vitro, CC-99677 inhibited tumor necrosis factor (TNF), interleukin (IL)-6, and IL-17 protein production in samples of monocytes and macrophages from AS patients and healthy volunteers via an mRNA-destabilization mechanism. In the in vitro model of tachyphylaxis, CC-99677 showed a differentiated pattern of sustained TNF protein inhibition compared with p38 inhibitors. CC-99677 reduced TTP phosphorylation and accelerated the decay of inflammatory cytokine mRNA in lipopolysaccharide-stimulated macrophages. Administration of CC-99677 to healthy volunteers was safe and well-tolerated, with linear pharmacokinetics and sustained reduction of ex vivo whole blood TNF, IL-6, and chemokine synthesis. Conclusions CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases and may overcome the limitations of p38 MAPK inhibition. Trial registration ClinicalTrials.gov NCT03554993.

Protein kinases: drug targets for immunological disorders

“…Besides p38 MAPK, an irreversible, covalent inhibitor of MAPK-activated protein kinase 2, known as CC-99677, is being studied in a phase I trial (NCT03554993) for potential use in ankylosing spondylitis and other inflammatory diseases 206 . An inhibitor (tilpisertib) of MAP3K8, which is downstream of TLRs and TNF receptor 5 , was studied in ulcerative colitis but the study was terminated because “a new molecular entity was able to achieve greater target coverage” (NCT04130919).…”

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

“…The utility of S N Ar chemistry in drug discovery has recently been highlighted by translational studies from researchers at Bristol Myers Squibb disclosing the development and characterization of clinical candidate CC-99677 ( 88 , gamcemetinib, Figure ). , This compound was rationally designed as a MAPKAPK2 (MK2) kinase inhibitor containing a 2-chloro­pyrimidine as the electrophilic moiety to irreversibly address the non-conserved Cys140 at the hinge region of the kinase ATP-binding site. MS experiments confirmed a covalent modification of MK2 as well as the S N Ar-based mechanism with the displacement of the chlorine atom.…”

Revisiting p38 Mitogen-Activated Protein Kinases (MAPK) in Inflammatory Arthritis: A Narrative of the Emergence of MAPK-Activated Protein Kinase Inhibitors (MK2i)

“…The CC-99677 molecule was also used in rat experimental spondyloarthritis and was found to be efficacious, and 4–300 mg doses in healthy human volunteers indicated sustained TNFα levels with a favorable safety profile [ 88 ]. They further investigated CC-99677 in PBMCs of healthy donors and in patients diagnosed with AS in a first-of-its-type study with 37 donors randomly assigned to either placebo or the drug molecule [ 89 ]. They observed that the production of TNFα, IL-6, and IL-17 was inhibited in monocytes and macrophages in healthy donors and AS patients via a mRNA-destabilizing mechanism.…”